title: Loss of mitochondrial complex I activity potentiates dopamine neuron death induced by microtubule dysfunction in a Parkinson's disease model.
abstract: Mitochondrial complex I dysfunction is regarded as underlying dopamine neuron death in Parkinson's disease models. However, inactivation of the Ndufs4 gene, which compromises complex I activity, does not affect the survival of dopamine neurons in culture or in the substantia nigra pars compacta of 5-wk-old mice. Treatment with piericidin A, a complex I inhibitor, does not induce selective dopamine neuron death in either Ndufs4(+/+) or Ndufs4(-/-) mesencephalic cultures. In contrast, rotenone, another complex I inhibitor, causes selective toxicity to dopamine neurons, and Ndufs4 inactivation potentiates this toxicity. We identify microtubule depolymerization and the accumulation of cytosolic dopamine and reactive oxygen species as alternative mechanisms underlying rotenone-induced dopamine neuron death. Enhanced rotenone toxicity to dopamine neurons from Ndufs4 knockout mice may involve enhanced dopamine synthesis caused by the accumulation of nicotinamide adenine dinucleotide reduced. Our results suggest that the combination of disrupting microtubule dynamics and inhibiting complex I, either by mutations or exposure to toxicants, may be a risk factor for Parkinson's disease.
authors.affiliation: Department of Environmental and Occupational Health Sciences, Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, WA 98195, USA.
authors.forename: Won-Seok
authors.initials: WS
authors.lastname: Choi
authors.forename: Richard D
authors.initials: RD
authors.lastname: Palmiter
authors.forename: Zhengui
authors.initials: Z
authors.lastname: Xia
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000502:physiology*; D009243:NAD / Q000378:metabolism / Q000502:physiology; D009410:Nerve Degeneration / Q000209:etiology*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors
chemical_list: C534449:Ndufs4 protein, mouse; D017382:Reactive Oxygen Species; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D012402:Rotenone; D009243:NAD; D042967:Electron Transport Complex I; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine